The objective of this explorative R21 proposal is to explore the cellular and molecular basis for the neuropsychiatric effects of the anti-viral cytokine interferon-alpha (IFN-alpha). Depression is a major health challenge worldwide with largely unknown etiology and pathophysiology. Therapeutic application of high doses of IFN-a has been shown to induce severe neuropsychiatric side effects in patients, especially depression. It is the number one reason for discontinuation of effective therapy in patients with disorders such as chronic viral infections and various malignancies. Nevertheless, very little is known about the underlying cellular and molecular basis for IFN-alpha-induced depression and other neuropsychiatric complications. Our working hypothesis is that chronic IFN-alpha will cause similar neurobehavioral abnormalities in mice directly associated with alterations of monoamine neurotransmission, which are mediated by a direct action of IFN-alpha in the brain. To test this, an interdisciplinary approach will be employed to: 1) establish a mouse model in which to assess the neurobehavioral impact of pharmacological treatment with IFN-alpha by peripheral administration; 2) examine the impact of IFN-a on the neurochemistry of the brain (e.g., neurotransmitters and their metabolites) and its relationship to specific neurobehavioral changes; and 3) examine receptor-mediated cell signaling in the brain and peripheral tissues after pharmacological treatment with IFN-alpha by analyzing IFN-alpha signal transduction and downstream IFN-a-regulated genes at both the transcriptional and protein levels. The action site of IFN-a for its neurobehavioral/neurochemical alterations will thereby be defined. By establishing a mouse model for the study of IFN-alpha-induced neurobehavioral changes and elucidating the cellular and molecular mechanisms underlying these actions, these proposed studies will not only advance our understanding of the relationship between IFN-alpha and neuropsychiatric disorders, but may also point to novel strategies to alleviate the CNS complications of this cytokine